Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 6, Pages 1999-2004Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1221068110
Keywords
cancer evolution; mathematical modeling; stochastic processes; driver mutation; passenger mutation
Categories
Funding
- National Institutes of Health (NIH) [T32 CA009337]
- NIH/National Cancer Institute [5P30 CA006516-46]
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Although it has been hypothesized that some of the somatic mutations found in tumors may occur before tumor initiation, there is little experimental or conceptual data on this topic. To gain insights into this fundamental issue, we formulated a mathematical model for the evolution of somatic mutations in which all relevant phases of a tissue's history are considered. The model makes the prediction, validated by our empirical findings, that the number of somatic mutations in tumors of self-renewing tissues is positively correlated with the age of the patient at diagnosis. Importantly, our analysis indicates that half or more of the somatic mutations in certain tumors of self-renewing tissues occur before the onset of neoplasia. The model also provides a unique way to estimate the in vivo tissue-specific somatic mutation rates in normal tissues directly from the sequencing data of tumors. Our results have substantial implications for the interpretation of the large number of genome-wide cancer studies now being undertaken.
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